Prejunctional modulation by angiotensins of noradrenaline release from sympathetic neurons in isolated rabbit aorta.
The aims of the present work were to compare the modulating effect of angiotensins I, II, III, IV and (1-7) [AI, AII, AIII, AIV and A(1-7) respectively] on stimulation-evoked noradrenaline release from postganglionic sympathetic nerves in rabbit isolated aorta; to examine the influence of inhibiting the neuronal and extraneuronal uptake of noradrenaline on the modulating effect of AII and thirdly, to determine the role of angiotensin converting enzyme (ACE) in the modulating effects of AI and AII and the role of aminopeptidases A and M in the effects of AII and AIII. Rings of aorta were preloaded with (-)-3H-noradrenaline and then subjected to electrical field stimulation. Cumulative addition of AI (10(-8)-10(-6) M), AII (3 x 10(-11)-10(-8) M) and AIII (3 x 10(-10)-10(-6) M) enhanced the stimulation-evoked 3H-overflow up to 142, 165 and 188% respectively. The order of potency was AII > AIII > AI. AIV (10(-10)-10(-7) M) and A(1-7) (10(-10)-10(-7) M) caused no change. Single concentrations (10(-9)-10(-7) M) of AI, AII and AIII caused initial enhancement which subsequently decreased, i.e. development of tachyphylaxis. The effect of AII was independent of stimulation frequency at 1-10 Hz, but absent at 30 Hz. Cocaine (3 x 10(-5) M) plus corticosterone (4 x 10(-5) M) did not alter the enhancing effect of AII. CaNa2EDTA (3 x 10(-5) M) did not alter the enhancing effect of AI. Captopril (10(-6) and 10(-5) M) and lisinopril (10(-6) M) attenuated the enhancing effect of AI. Captopril and lisinopril (both 10(-6) and 10(-5) M) did not alter the enhancing effect of AII. Captopril (10(-7)-10(-4) M) and lisinopril (10(-7)-10(-4) M) themselves did not alter the stimulation-evoked 3H-overflow. Amastatin (10(-5) M) increased the enhancement seen with AIII (3 x 10(-11)-10(-9) M) but did not alter the enhancing effect of AII (10(-9)-10(-8) M). Amastatin (10(-9)-10(-5) M) had no effect on the stimulation-evoked 3H-overflow. It is concluded that AI, AII and AIII facilitate the stimulation-evoked 3H-noradrenaline release to various degrees (relative order of potency: AII > AIII > AI and of efficacy: AIII > AII > AI). The estimates may be compromised by the development of tachyphylaxis. The facilitation by AII was independent of the neuronal and extraneuronal uptake mechanisms. The action of AI is in part due to its conversion to AII. The effect of AIII was probably underestimated due to its degradation to AIV. AII is apparently not a substrate for aminopeptidase M.
Storgaard
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Department of Pharmacology, School of Medicine, Odense University, Denmark.
Nedergaard
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OA
D000626:Aminopeptidases / Q000378:metabolism*; D000809:Angiotensins / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000294:innervation / Q000378:metabolism; D004558:Electric Stimulation; D005260:Female; D043384:Glutamyl Aminopeptidase; D008297:Male; D063208:Methionyl Aminopeptidases; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D011817:Rabbits; D017661:Receptors, Presynaptic / Q000187:drug effects / Q000502:physiology*
D000809:Angiotensins; D017661:Receptors, Presynaptic; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases; D043384:Glutamyl Aminopeptidase; D007703:Peptidyl-Dipeptidase A; D009638:Norepinephrine